Methyl acrylate intermolecular

On the other hand, many reactions are known where in a first intermolecular step a functionality is introduced which than can undergo an intramolecular reaction. A nice example is the reaction of dienone 0-34 with methyl acrylate in the presence of diethylaluminum chloride to give the bridged compound 0-35 (Scheme 0-11). The first step is an intermolecular Michael addition, which is followed by an intramolecular Michael addition. This domino process is the key step of the total synthesis of valeriananoid A, as described by Hagiwara and coworkers [21]. 

Inter [4+2]/inter [3+2] The tandem intermolecular [4+2]/intermolecular [3+2] cycloadditions create bicyclic nitroso acetals with up to six stereogenic centers, which can be controlled by the choice of the stereochemistry of each component and the Lewis acids. The nitronate derived from 2-nitrostyrene and 1-trimethylsilyloxycyclohexene reacts with methyl acrylate to give the nitroso acetal in good yield and high diastereoselectivity (Eq. 8.107).154... 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from l-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the l-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. 

Generally, the intermolecular Heck reaction between 2-iodo-, 4-iodo- and 5-iodo-l-methylimidazoles and olefins suffers from low yields (< 25%). Therefore, these transformations are of limited synthetic utility [29]. In one case, variable yields for adduct 62 (15-58%) were observed for the Heck reaction of 5-bromo-l-methyl-2-phenylthio-lf/-imidazole (61) and a large excess of methyl acrylate [42]. 

K. The rearrangement from 27 to the more stable, primary alkyl regioisomer 29 was shown to be intermolecular. This is thought to occur via the unobserved hydride 28, since addition of unlabeled methyl acrylate leads to the equilibrium distribution of label in 29 (28 exchanges acrylate ligands with the acrylate pool). 

In Rao s total synthesis of niphatesines, a key intermediate 91 was elaborated from an intermolecular Heck reaction of 3-bromopyridine with non-8-en-ol <93TL8329>. In another case, Bracher et al. synthesized a natur ly occurring P-carboline, infractine (93), from p-carboline-l-triflate (92) in a two step process consisting of a Heck reaction with methyl acrylate followed by a hydrogenation <95PHA182>. Their approach provided an expeditious route to infractine, although the Heck reaction was low yielding. 

The inter- and intramolecular Heck reactions provide other routes to substituted pyridines . Although electron-deficient 2-bromopyridines are resistant to substitution under Heck conditions, the aminopyridine 142 affords a high yield of the adduct 143 (Equation 68) <1998T6311>. The intermolecular Heck reaction of a 3-pyridyltriflate with ethyl acrylate is accelerated by LiCl <1999SL804>. An efficient Heck vinylation of 3-substituted-2-bromo-6-methylpyridines with methyl acrylate has been developed <2005T4569>. 

Chiral phosphines were examined for intermolecular MBH reaction of pyrimidine 5-carboxaldehyde and methyl acrylate (Table 5.9) [85]. Most of the catalysts afforded no, or low, enantioselectivity. The best ee-value was obtained with BINAP catalyst (Table 5.9, entry 4), which afforded product in ee-values up to 44%. 

The scope of this approach was widened by the observation of excellent enantioselectivities in intermolecular [2+ 2]-photocycloaddition reactions with various alkenes [62,71]. In the presence of an excess amount of alkene, 4-me thoxy-2-quinolone (57) was converted with high chemo- and regioselectivity to the exo and endo cyclobutanes 59 and 60. With 4-penten-1-ol (58a), allyl acetate (58b), methyl acrylate (58c), and vinyl acetate (58d), the exo diastereomers 59a-d were formed with high simple diastereoselectivity and in high yields (80-89%), Under optimized irradiation conditions (2.4 eq. of host 44 or ent-44, — 60°C), high enantiomeric excesses were achieved in all instances, as depicted in Scheme 22. These enantiomeric excesses are unprecedented for an intermolecular photochemical reaction. 

Conditions for the intermolecular aza-double Michael reaction of acrylamides leading to functionalized 2-piperidones have been developed, as exemplified by the conversion of 225 to 226. Of particular interest was the use of a cross reaction of amide 227 with methyl acrylate to give 228. This 2-piperidone was readily converted to (+)-paroxetine 229 (Scheme 66) <05JOC3957>. 

Methylation and benzylation of the pyrrolidine dienamine of 3-methyl-A "-2-octa-lone gives a mixture of N- and jS-alkylated products in protic and aprotic solvents. However, the position of attack by acrylonitrile and methyl acrylate is solvent-dependent. In protic solvents the / -alkylated octalone is obtained on hydrolysis, whereas in aprotic solvents the -alkylated product is produced (Scheme 7). This change in the regioselectivity arises from the C-3 methyl group being forced into a quasi-axial orientation because of allylic strain in the equatorial orientation. As a consequence the carbanionic centre in the initially formed zwitterion 6 cannot be neutralized by an internal proton transfer of an axial proton at C-3. In protic solvents intermolecular protonation renders the reaction irreversible, but in aprotic solvent reversion to starting material occurs. This allows 5- or -alkylation to occur and this is rendered irreversible by internal proton transfer from the 6 - or 5-position, respectively, to the carbanionic centre in the resulting zwitterion (Scheme 7). 

The radical cyclization reactions are clean, giving high yields of the cyclized products. It is of interest that the A-aziridinylimine can be used as a radical precursor, which involves the intermolecular addition of n-Bu3Sn radical to the N-aziridinylimino group to generate the a-BuaSn-substituted carbon-centered radical. One of the most exciting results is obtained by the radical cyclization of N-aziridinylimine in the presence of an activated olefin such as acrylonitrile or methyl acrylate. This example shows the formation of two consecutive carbon-carbon bonds indicated by solid lines (Scheme 9). This unprecedented approach is unique... 

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